RUNX2

Researchers have discovered a suite of genes that influence head shape in humans. These findings help explain the diversity of human head shapes and may also offer important clues about the genetic basis of conditions that affect the skull, such as craniosynostosis. Researchers at the University of Pittsburgh and KU Leuven have discovered a suite of genes that influence head shape in humans. These findings, published this week in Nature Communications, help explain the diversity of human head shapes and may also offer important clues about the genetic basis of conditions that affect the skull, such as craniosynostosis. By analyzing measurements of the cranial vault -- the part of the skull that forms the rounded top of the head and protects the brain -- the team identified 30 regions of the genome associated with different aspects of head shape, 29 of which have not been reported previously. "Anthropologists have speculated and debated the genetics of cranial vault shape since the early 20th century," said co-senior author Seth Weinberg, Ph.D., professor of oral and craniofacial sciences in the Pitt School of Dental Medicine and co-director of the Center for Craniofacial and Dental Genetics. "We knew from certain rare human conditions and animal experiments that genes play an important role in vault size and shape, but very little was known about the genetic basis for typical features we see in the general population, such as what makes someone's head long and narrow versus short and wide. This study reveals some of the key genes driving variation in this part of the human body." According to the researchers, one application of better understanding the factors that drive natural variation in human head shape is informing paleoanthropology studies, potentially shedding light on the early development of modern humans. Weinberg and colleagues used magnetic resonance (MR) scans from more than 6,000 adolescents to extract 3D surfaces corresponding to the cranial vault. After dividing the 3D vault surfaces into incrementally smaller anatomical subparts and quantifying the shape of these subparts, they tested more than 10 million genetic variants for evidence of statistical association with measures of vault shape. "Previous genetic studies of the cranial vault involved a small number of relatively simple measures," added Weinberg. "While such measures are often easy to obtain, they may fail to capture features that are biologically relevant. Our analysis used an innovative approach capable of describing 3D vault shape in much more comprehensive and nuanced ways. This approach increased our ability to find genetic associations." An important discovery was that many of the strong associations are near genes that play key roles in the early formation of the head and face and regulation of bone development. For example, variants in and near the gene RUNX2, a major player in coordinating development of the skull, were associated with multiple aspects of vault shape. While some genes, including RUNX2, had global effects involving the entire vault, others showed more localized effects that only impacted a specific portion of the vault, such as the central forehead. When the researchers compared the 30 genomic regions associated with head shape across participants with European, African and Indigenous American ancestry, they found that the majority of genetic associations were shared across these different ancestral groups. Although the study focused on healthy participants, the findings may reveal important clues about the biological basis of diseases involving the cranial vault, according to Weinberg. One of these conditions is craniosynostosis, which occurs when the bones of the skull fuse too early while the brain is still growing rapidly. Without neurosurgery, craniosynostosis can cause permanent disfigurement, brain damage, blindness and even death. The team showed that variants near three genes associated with vault shape, BMP2, BBS9 and ZIC2, were also associated with craniosynostosis, suggesting that these genes could play a role in the development of the disease. "This kind of study is possible due to the availability of publicly funded resources," said Weinberg. "The original study that generated these MR scans is focused on understanding brain development and behavior. By creatively leveraging these resources, we have managed to advance discovery beyond that original scope." Other authors on the study were Seppe Goovaerts, Hanne Hoskens, Ph.D., Meng Yuan, Dirk Vandermeulen, Ph.D., all of KU Leuven; Ryan J. Eller, Ph.D., Noah Herrick, Ph.D., and Susan Walsh, Ph.D., all of Indiana University-Purdue University Indianapolis; Anthony M. Musolf, Ph.D., and Cristina M. Justice, Ph.D., both of the National Human Genome Research Institute; Sahin Naqvi, Ph.D., and Joanna Wysocka, Ph.D., both of Stanford University; Myoung Keun Lee, Heather L. Szabo-Rogers, Ph.D., Mary L. Marazita, Ph.D., and John R. Shaffer, Ph.D., all of Pitt; Paul A. Romitti, Ph.D., of the University of Iowa; Simeon A. Boyadjiev, M.D., of the University of California, Davis; Mark D. Shriver, Ph.D., of Penn State University; and Peter Claes, Ph.D., of KU Leuven and Murdoch Children's Research Institute. This research was supported by the National Institute of Dental and Craniofacial Research (R01DE027023, R01DE016886, R03DE031061 and X01HL14053) and the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health

Researchers have found that bone repair can be improved in mice with large bone lesions by injecting a combination of RNA encoding two different proteins. Their technique is a promising candidate for clinical use. This study provides new hope for patients with large bone lesions as a result of injury or surgery, in whom bone repair is often difficult to achieve. Although bones have the ability to regenerate and repair themselves, they are generally unable to do so when the injury is larger than a small break or chip. In a study just published in Inflammation and Regeneration, Japanese researchers have developed a technique for improving bone regeneration over large areas in rats -- and their findings may translate well to clinical settings. As most of us know from experience, bones can repair themselves after a minor break or fracture, leaving us as good as new. Unfortunately, after a larger injury -- or if a lot of bone needs to be removed because of something like a tumor -- bones often don't heal well. Although there are many different ways to improve bone repair over larger areas in animal models, very few techniques translate well into the clinic. A research team from Tokyo Medical and Dental University (TMDU) decided to tackle this challenge using vascular endothelial growth factor (VEGF), which improves regeneration of the blood circulatory system, and Runt-related transcription factor 2 (Runx2), which is important for bone regeneration. "We had already used these two factors to improve bone regeneration in mice in a previous study," explains senior author of the study Keiji Itaka. "But we injected DNA, which can insert itself into the body's genetic information, rather than RNA, which cannot; this meant that our findings had little clinical relevance because of the risks involved." In their new study, the researchers used messenger RNA encoding VEGF and Runx2. They first demonstrated that the combination of these two RNAs led to a better regenerative response in bone cells than each RNA alone. Next, they injected the RNA combination into rats with large jawbone lesions. After three weekly injections, the jawbones of these mice were almost completely healed, unlike those of control mice. Importantly, their technique may have similar results in a clinical setting and is likely to be safe for use in humans. "Our technique is especially promising for clinical use because of the coating that we used for the VEGF and Runx2 RNA," explains Maorui Zhang, lead author of the study. "Many previous studies have used lipid nanoparticles, but this coating leads to inflammation, limiting its clinical use. We used a coating that we had developed previously, known as polyplex nanomicelles, which leads to very little inflammation." Given that large bone injuries can be difficult to repair in the clinic, the findings of this study bring new hope to patients. The use of combinations of RNA coated in polyplex nanomicelles is potentially an effective, low-risk technique for improving bone repair in humans and has many promising clinical applications.

Researchers have identified the role of transcription factors Runx1 and Runx2 in the inhibition of fibrosis, the abnormal build-up of connective tissue with severe hematopoietic defects, in the bone marrow. Mice lacking both Runx1 and Runx2 in CAR cells, a major component of the hematopoietic stem cell niche, demonstrated severe myelofibrosis and defects in the production of blood cells. Runx1 and Runx2 may act as potential targets in the diagnosis and treatment of myelofibrosis. In your home, storing books on a bookshelf, tools in a tool box, and a broom in a broom cupboard makes it easy to access these items whenever you need them. Within the body, hematopoietic stem cells (HSCs) reside in their own specialized "spots" in the bone marrow known as HSC niches. Recently, researchers in Japan have identified genes that play a key role within these niches. In a new study published in Nature Communications, researchers led by Osaka University have shed new light on the role of transcription factors Runx1 and Runx2 in the bone marrow microenvironments known as HSC niches. HSC niches are essential for the maintenance of HSCs, which give rise to blood cells. A major component of HSC niches is a cell type known as CXC chemokine ligand 12-abundant reticular (CAR) cells. CAR cells express signaling molecules known as cytokines that are important for the maintenance of hematopoietic stem and progenitor cells (HSPCs). The team previously found that CAR cells express a transcription factor called Runx2, which is known to play a role in the development of the skeleton. In this study, they newly found that CAR cells also express Runx1, which is known to be essential for development of hematopoietic stem cells. However, it is completely unknown how Runx transcription factors function in the maintenance of HSC niches, which prompted the research team to investigate this role. "To evaluate the impact of Runx transcription factors on the bone marrow, we used mouse models in which Runx1 and/or Runx2 was deleted specifically within CAR cells," says lead author Yoshiki Omatsu. The researchers found that mice lacking Runx1 in mesenchymal cells including CAR cells showed normal bone and bone marrow development, while mice lacking Runx2 exhibited normal CAR cells and bone marrow but short and immature bone. However, mice lacking both Runx1 and Runx2 in CAR cells showed a significant reduction of HSPCs and immune cells, along with an increase in fibrosis (the abnormal build-up of connective tissue) in the bone marrow, a hallmark of a condition known as myelofibrosis. "Our results strongly indicate the essential role of Runx1 and/or Runx2 in the inhibition of fibrosis and maintenance of the HSC niche," says senior author Takashi Nagasawa. The research team also found that in a mouse model of primary myelofibrosis, expression of Runx1 and Runx2 was reduced while expression of fibrotic genes was increased, further highlighting the role of Runx1 and Runx2 in the inhibition of fibrosis in the bone marrow. Although more work is needed on the topic, these findings suggest that Runx1 and Runx2 may be potential targets for the diagnosis and treatment of myelofibrosis.